Theory (Newlin & Thomson, 1990) and empirical evidence (Newlin & Thomson, 1991, 1999) have linked greater Diphasic effects of alcohol to heightened vulnerability to alcohol use disorders (AUDs). The proposed research will evaluate this relationship, as well as neurogenetic mechanisms that mediate alcohol response, using powerful brain imaging and molecular-genetic techniques. Specifically, the longterm goals of the research are to: (1) test a model developed by the PI (Newlin) concerning brain mechanisms that may mediate the biphasic response to alcohol; (2) determine brain pharmacokinetics of alcohol; and (3) relate biphasic regional cerebral blood flow (rCBF) and brain alcohol levels to addiction vulnerability genotypes. This research will further our understanding of brain responses to alcohol and their relationship to genetic variants that confer vulnerability. A functional; magnetic resonance imaging (fMRI) experiment using arterial spin labeling (ASL, Wang et al., 2004) to measure rCBF and regional brain ethanol levels (rBEL) (adapted from Fein & Meyerhoff, 2000) will test aspects of this model. Right-handed non-problematic drinkers (N = 32) will participate in 3 sessions with fMRI, before and after drinking (double-blind) alcohol (either 0.375 or 075 g/kg) or placebo. In addition to venous blood, BEL will be assessed regionally, temporally (over the time-course), and as a function of dose. We predict greater left than right prefrontal and ventral striatal rCBF, tachycardia, and greater Stimulant scale scores on the Biphasic Alcohol Effects Scale during the rising blood alcohol curve (50% then 85% of that individual's peak BEL), as well as overall greater ventral striatal and limbic rCBF than prefrontal Rcbf during the rising curve. We predict the opposite pattern for the falling curve. Participants will be stratified based on their genotypes at addiction-associated genomic loci; half will have high genetic vulnerability to develop an ADD; the other half, who will be matched to the high-risk group, will have low susceptibility. This approach is based on findings from recent studies implicating molecular markers in the vicinity of ALDH genes and at other genomic regions in the development of an AUD and other addictions. Therefore, this study will test one potential brain pathway-exaggerated biphasic rCBF responses-in the genetic transmission of AUDs.